Over the last period of funding our focus has been to understand the mechanism of action of rapamycins, and develop rational combinations in the context of these mTOR inhibitors. This work was based on our earlier studies demonstrating IGF-II/IGF1R signaling in rhabdomyosarcomas, and that rapamycin potently inhibited proliferation of these cells. We have now identified a pathway downstream of mTOR that signals survival, and that cells defective in p53 function undergo apoptosis when treated with rapamycin in the absence of exogenous IGF-I. Reagents that selectively block IGF-IR signaling (both antibodies and small molecules with reasonable in vivo pharmacokinetics) are now available, and will be the focus of the work proposed: Hypothesis 1: Targeting the IGF-IR pathway in the context of mTOR inhibition will be effective if compensatory pathways are also blocked. Aim 1. To define the role of IGF-IR signaling in sarcoma and neuroblastoma xenografts. Hypothesis 2: That inhibition of Akt will be more effective in suppressing tumor-derived VEGF than mTOR inhibition, and that the combination of inhibitors in the IGF-IR pathway will be effective antitumor and antiangiogenic therapy. Aim 2. To define the role of IGF-IR/Akt/mTOR signaling in VEGF production and angiogenesis in models of childhood tumors in vitro and in vivo. Hypothesis 3: That molecular signatures at baseline (untreated) or post treatment with drugs/antibodies targeting the IGF-IR pathway will define tumor responsiveness to treatment. Aim 3. To define potential biomarkers that predict response to IGF-IR-directed therapies using expression and proteomics profiling. Successful completion of the aims will define the relevance of the IGF-I receptor as a therapeutic target, in the absence of presence of mTOR inhibition, and potentially identify tumor-specific changes that compensate for IGF-IR inhibition as potential additional therapeutic targets. The overall objective is to test therapeutic strategies in appropriate xenograft models, and use the results for design of clinical protocols.